Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/429—Thiazoles condensed with heterocyclic ring systems
  • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems

Definitions

• This invention relates to new antibacterial synergistic compositions containing penicillin derivatives or cephalosporin derivatives, methods for the preparation of such compositions and a method for the treatment of infectious diseases.
• this invention relates to an antibacterial synergistic composition consisting essentially of a mixture of:
• composition contains the compounds of formula I and II in a weight ratio varying from 10:1 to 1:10, preferably varying from 2:1 to 1:2.
• the composition can be incorporated in a pharmaceutically acceptable carrier.
• a further surprising finding is that bacterial organisms may develop resistance to a combination of compounds of the formula I and II less readily than to either of the compounds alone.
• the group R is preferably a group of the formula ##STR9## wherein X is --H, --NH 2 , --N 3 , --COOH or --SO 3 H, provided that the compound of the formula I is a penicillin.
• the group R is preferably a group selected from NC--CH 2 --, ##STR10##
• penicillins and cephalosporins with the general formula I are known to have strong antibacterial activity and such penicillins and cephalosporins have been extensively used for the treatment of infectious diseases caused by Gram-positive and Gram-negative bacteria.
• the preferred compounds of the formula I are the penicillins: benzyl-penicillin, 6-(D- ⁇ -aminophenylacetamido)penicillanic acid, 6-(D- ⁇ -azidophenylacetamido)penicillanic acid, ⁇ -carboxybenzylpenicillin, ⁇ -hydroxysulphonyl-benzylpenicillin, and the cephalosporins which are illustrated by the specific combinations of the groups R and R 3 in the following table:
• the penicillins or cephalosporins of the formula I may also include such known esters thereof which are rapidly hydrolyzed in vivo.
• suitable ester groups i.e. the group R 2 in the formula I above, are acyloxy-alkyl groups, e.g. the acetoxy-methyl, the pivaloyloxy-methyl or the 1"-acetoxy-ethyl group; or alkyloxycarbonyloxy-alkyl groups e.g. the ethoxycarbonyloxymethyl or the 1'-ethoxycarbonyloxy-ethyl group.
• ester groups can be described by the formula ##STR21## wherein A is hydrogen or methyl, and B is alkyl or alkoxy. Preferably the group B should not contain more than four carbon atoms. The preferred meaning of the group A and B is methyl and ethoxy, respectively.
• Penicillin and cephalosporin esters of this type are known e.g. from German Patent Applications P 21 44 457.5; P 23 12 041.4; P 23 11 328.2; P 23 12 042.5 and P 23 11 346.4.
• Penicillins of the general formula II also exhibit strong antibacterial activity, particularly against Gram-negative organisms. These until recently unknown penicillins have been described in Dutch Patent Application No. 7,016,435 and in British Patent No. 1,293,590.
• Examples of compounds of the formula II are 6-[(hexahydro-1H-azepin-1-yl)methyleneamino]-penicillanic acid, 6-[(piperidyl-1)methylenamino]-penicillanic acid, 6-[(hexahydro-1(2H)-azocinnyl)methyleneamino]-penicillanic acid, and 6-[(N-ethyl-N-isopropylamino)methyleneamino]-penicillanic acid.
• the preferred penicillins of the formula II are those wherein the groups R 5 and R 6 , when taken together with the adjacent nitrogen atom, represent a ring system of the formula ##STR22## wherein n is 5, 6 or 7. Preferably n is 6.
• the penicillin of the formula II may be in the form of a known ester thereof, which is rapidly hydrolyzed in vivo.
• suitable penicillin esters included in the formula II are those wherein the group R 4 is an acyloxy-alkyl group, e.g. the acetoxy-methyl, the pivaloyloxy-methyl or the 1"-acetoxy-ethyl group; or an alkyloxycarbonyloxy-alkyl group e.g. the ethoxycarbonyloxymethyl or the 1'-ethoxycarbonyloxyethyl group.
• these ester groups can be described by the formula ##STR23## wherein A and B have the meaning given above.
• Penicillin esters of this type, and included in the formula II are known e.g. from Dutch Patent Applications No. 7,016,435 and 7,303,434.
• Examples of preferred penicillin esters of the formula II are pivaloyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)methyleneamino]penicillanate, acetoxy-methyl 6-[(hexahydro-1H-azepin-1-yl)methyleneamino]penicillanate, pivaloyloxymethyl 6-[(hexahydro1(2H)-azocinnyl)methyleneamino]penicillanate, ethoxycarbonyloxymethyl 6-[(hexahydro-1H-azepin-1-yl)methyleneamino]penicillanate, 1'-ethoxycarbonyloxy-ethyl 6-[(piperidyl-1)methyleneamino]penicillanate, 1'-acetozyethyl 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]penicillanate, 1'-ethoxycarbonyl
• the composition according to the invention can be prepared by various mixing operations well known for the preparation of compositions containing penicillins or cephalosporins.
• the mixing operations may be accompanied by chemical reactions between the constituents of the new composition.
• the mixing operations may also be combined with the simultaneous preparation of esters and salts of the penicillins and cephalosporins included in the composition of the invention.
• the new composition according to the invention in some respects can be regarded as one new chemical individual, as the new composition has an antibacterial activity which is unique and widely different from the acitivity which can be deduced from a calculation based upon the activity of the single constituents.
• composition of the present invention may be administered either orally or by injection.
• the composition may have optionally incorporated therewith other substances, e.g. pharmaceutically acceptable solid or liquid carriers or diluents and may be in any of the conventional pharmaceutical forms known to the art for penicillin therapy, for example compositions suitable for oral administration, for example tablets, granules, capsules, dispersible powders for the preparation of aqueous dispersions for oral use, solutions, suspensions or emulsions, or compositions suitable for parenteral administration, for example aqueous or non-aqueous solutions or suspensions, or dispersible powders for the preparation of sterile aqueous dispersions, or compositions suitable for topical administration, for example ointments.
• compositions suitable for oral administration for example tablets, granules, capsules, dispersible powders for the preparation of aqueous dispersions for oral use, solutions, suspensions or emulsions, or compositions suitable for parenteral administration, for example aqueous
• compositions according to the invention show low toxicity and are well tolerated.
• the composition of the invention is for example administered in amounts corresponding to 5 to 200 mg/kg/day, of the active ingredients of the composition, preferably in the range of 10 to 100 mg/kg/day in divided dosages, e.g. two, three or four times a day. They are e.g. administered in dosage units containing e.g. 175, 350, 500 and 1000 mg of the active ingredients of the composition.
• Example 1 Using the technique described in Example 1 the in vitro effect of combinations of 6-(D- ⁇ -aminophenylacetamido)-penicillanic acid (I) and 6-[(N,N-diethylformamidino)-N'-amino]penicillanic acid (VII) in the ratios 1:1, 1:2 and 2:1 against clinically isolated strains of Coliforma, Klebsiella-Enterobacter and Proteus was determined in serial dilution tests.
• 6-(D- ⁇ -aminophenylacetamido)-penicillanic acid (I) and 6-[(N,N-diethylformamidino)-N'-amino]penicillanic acid (VII) in the ratios 1:1, 1:2 and 2:1 against clinically isolated strains of Coliforma, Klebsiella-Enterobacter and Proteus was determined in serial dilution tests.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Agricultural Chemicals And Associated Chemicals (AREA)

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Cited By (17)

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Citations (1)

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• 1971
  • 1971-11-01 GB GB5067571A patent/GB1405886A/en not_active Expired
• 1972
  • 1972-10-18 DE DE2265533A patent/DE2265533C2/de not_active Expired
  • 1972-10-18 DE DE2250993A patent/DE2250993C2/de not_active Expired
  • 1972-10-25 AT AT910172A patent/AT324550B/de not_active IP Right Cessation
  • 1972-10-25 AU AU48126/72A patent/AU474065B2/en not_active Expired
  • 1972-10-26 NL NLAANVRAGE7214478,A patent/NL176525C/xx not_active IP Right Cessation
  • 1972-10-31 SE SE7214083A patent/SE401087B/xx unknown
  • 1972-10-31 FR FR7238691A patent/FR2158427B1/fr not_active Expired
  • 1972-11-01 JP JP47108956A patent/JPS4852917A/ja active Pending
• 1979
  • 1979-07-05 FI FI792124A patent/FI792124A7/fi not_active Application Discontinuation
  • 1979-12-27 NO NO794295A patent/NO794295L/no unknown
• 1987
  • 1987-07-02 US US07/069,787 patent/US4956179A/en not_active Expired - Fee Related

Patent Citations (1)

Non-Patent Citations (2)

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